Role of prostaglandin E2 in the synthesis of the pro-inflammatory cytokine interleukin-6 in primary sensory neurons: an in vivo and in vitro study

Following various types of nerve injury, cyclooxygenase 2 and prostaglandin E2 (PGE2) are universally and chronically up-regulated in injured nerves and contribute to the genesis of neuropathic pain. Persistent high levels of PGE2 likely exert chronic effects on nociceptive dorsal root ganglion (DRG) neurons. In the present study, we tested the hypothesis that injured nerve-derived PGE2 contributes to the up-regulation of the pro-inflammatory cytokine interleukin-6 (IL-6) in DRG neurons following partial sciatic nerve ligation. In naive adult rats, IL-6 was expressed in only a few small size DRG neurons which all co-expressed EP4 receptors. Partial sciatic nerve ligation increased and shifted IL-6 expression from small to medium and large size damaged DRG neurons. Perineural injection of a selective cyclooxygenase 2 inhibitor or a selective EP4 receptor antagonist significantly suppressed the up-regulation of IL-6 in DRG, suggesting that injured nerve derived PGE2 contributes to the de novo synthesis of IL-6 in DRG neurons through EP4 receptors. In cultured sensory ganglion explants, a stabilized PGE2 analog increased IL-6 mRNA and protein levels through the activation of EP4, protein kinase A, protein kinase C, extracellular regulated protein kinase/MAPK, cAMP response element binding protein and NFkappaB signalling pathways. Taken together, these data indicate that facilitating the de novo synthesis of pain-related cytokines in injured medium and large size DRG neurons is a novel mechanism underlying the role of injured nerve derived PGE2 in the genesis of neuropathic pain

Keywords : Adult,Analysis of Variance,Animals,antagonists & inhibitors,Biphenyl Compounds,classification,CREB-Binding Protein,Cyclooxygenase 2,Cyclooxygenase Inhibitors,Cytokines,cytology,Dinoprostone,Dose-Response Relationship,Drug,drug effects,Enzyme Inhibitors,Enzyme-Linked Immunosorbent Assay,Ganglia,Spinal,genetics,injuries,Interleukin-6,Ligation,Male,metabolism,methods,Neurons,Nitrobenzenes,Organ Culture Techniques,Pain,Pain Measurement,Pain Threshold,pathology,pharmacology,physiology,Protein-Serine-Threonine Kinases,Rats,Rats,Sprague-Dawley,Reaction Time,Receptors,Prostaglandin E,EP4 Subtype,Sciatic Nerve,Sciatic Neuropathy,Sensory Receptor Cells,Signal Transduction,Sulfonamides,Time Factors,Up-Regulation,, Prostaglandin,E2, local acupuncture clinics

Date of Publication : 2011 Sep

Authors : St-Jacques B;Ma W;

Organisation : Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada

Journal of Publication : J Neurochem

Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/21371033

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